ASCO 2018: The Complete Genomic Landscape of Metastatic Prostate Cancer Pinpoints Clinically Targetable Subgroups

Chicago, IL ( There is a significant degree of heterogeneity in the pathophysiology and cancer biology of prostate cancer, as well as other malignancies. Unfortunately, current histopathologic classifications have limitations, and while they can predict clinic course relatively well, there continues to be some degree of subjectivity and interobserver variability in classification – and tumor heterogeneity even within a single histopathologic class. The hope has long been that molecular classification systems, either alone or in combination with current histopathology and clinical variables, can help overcome some of those deficiencies.

In this study, the authors from multiple institutions in the Netherlands provide a complete genomic analysis of patients with metastatic prostate cancer, in order to identify clinically targetable subgroups – groups that may benefit for therapies other than the standard of care. Where they wanted to go above and beyond other studies is that they analyzed both primary and metastatic burden, as previous studies have demonstrated that genomic alterations obtained from primary and metastatic prostate cancer (mPCa) sites vary widely.

They obtained fresh-frozen tissue biopsies of 145 patients with mPCa, which were then completely analyzed by whole-genome sequencing (WGS) to a minimum depth base coverage of 90x for tumor samples and 30x for peripheral blood (reference). Biopsy sites included bone, lymph node and viscera. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and chromosomal rearrangements. Each of their incidence was compared to results reported for primary disease (Fraser et al. Nature 2017).1 The work by Fraser et al. was for 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate cancers with similar clinical risk profile. Unfortunately, these tumors had a lack of single actionable targets. However, they did find that many molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and noted that their signature comprised of these aberrations outperformed previously described prognostic biomarkers.

In terms of the patient population, median age was 68. In this study, they focused on the metastatic sites alone. Median tumor cell content of the biopsied lesions was 60% (95% CI: 56-64%). Patient data ***

In terms of genomic analysis, median single nucleotide variant (SNV) burden was 2.86 SNVs per million base pairs (Mbp; 95% CI: 2.44-2.88) compared to 0.53 SNVs per Mbp in primary disease. Structural variants were common, except insertions. 8q and Xq (including AR) were frequently amplified.

High SNV and (insertion-deletions) InDel load correlated with microsatellite instability (MSI) mutational signatures (8/153 tumors). This carries potential implications for therapeutic plans – as these patients may be more sensitive to immune therapy.

Clinically targetable subgroups:
1. 12 patients with high tumor mutational burden were identified, of whom 11 had MSI/MMRd gene signatures. They also had enriched somatic mutations in DNA repair genes.
2. Signature 3 (BRCA-ness) was identified in 27 patients, of whom 17 had somatic BRCA ½ alteration.
3. AR and MYC were frequently amplified. PTEN and RB1 were frequently deleted.
4. TMPRSS2-ERG fusion identified in 66 patients

Median number of inter-chromosomal rearrangements was 58 (95% CI: 49-67) compared to 19 in primary disease. Specifically, they found a total of 69 and 62 alterations, including SNVs and CNAs, in the genes AR and TP53, respectively, which are both important drivers in mPCa.

1. They are comparing their metastatic disease sites to primary tumors from other patients. It would have been nice to compare it to primary tumors from the same patients!

Presented by: Lisanne Francisca van Dessel

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

1. Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler LE, Livingstone J, Huang V, Shiah YJ, Yousif F, Lin X, Masella AP, Fox NS, Xie M, Prokopec SD, Berlin A, Lalonde E, Ahmed M, Trudel D, Luo X, Beck TA, Meng A, Zhang J, D'Costa A, Denroche RE, Kong H, Espiritu SM, Chua ML, Wong A, Chong T, Sam M, Johns J, Timms L, Buchner NB, Orain M, Picard V, Hovington H, Murison A, Kron K, Harding NJ, P'ng C, Houlahan KE, Chu KC, Lo B, Nguyen F, Li CH, Sun RX, de Borja R, Cooper CI, Hopkins JF, Govind SK, Fung C, Waggott D, Green J, Haider S, Chan-Seng-Yue MA, Jung E, Wang Z, Bergeron A, Dal Pra A, Lacombe L, Collins CC, Sahinalp C, Lupien M, Fleshner NE, He HH, Fradet Y, Tetu B, van der Kwast T, McPherson JD, Bristow RG, Boutros PC.
Genomic hallmarks of localized, non-indolent prostate cancer. Nature. 2017 Jan 19;541(7637):359-364. doi: 10.1038/nature20788. Epub 2017 Jan 9.
2. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR. Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500(7463):415-21. doi: 10.1038/nature12477. Epub 2013 Aug 14. Erratum in: Nature. 2013 Oct 10;502(7470):258. Imielinsk, Marcin [corrected to Imielinski, Marcin].